This invention relates generally to methods and pharmaceutical formulations for treating patients at elevated cardiovascular risk, and more particularly relates to treatment of such patients with a combination of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin.
Many individuals are at an elevated risk of suffering serious to life-threatening cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and widespread throughout the world population. They include cigarette smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ transplant, and others. Many of these risk factors are mediated through atherosclerosis. There is a need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk of incurring a cardiovascular event in individuals who have these risk factors.
Olukotun et al., in U.S. Pat. No. 5,622,985, disclose that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (cholesterol-lowering drugs), particularly pravastatin, when used alone or with an angiotensin converting enzyme (ACE) inhibitor, decrease the risk of a second heart attack in a patient who has a substantially normal cholesterol level. The combination with an ACE inhibitor is optional, and no mention is made of combining HMG CoA reductase inhibitors with other inhibitors of the renin-angiotensin system or with aspirin. In addition, the prevention of cardiovascular events other than second heart attacks is not considered.
Similarly, McGovern et al., in U.S. Pat. No. 5,140,012, disclose the use of pravastatin alone, or in combination with an ACE inhibitor, to prevent the onset of restenosis following angioplasty. HMG CoA reductase inhibitors other than pravastatin are not considered, and no mention is made of combining HMG CoA reductase inhibitors with other inhibitors of the renin-angiotensin system or with aspirin. The prevention of cardiovascular disorders other than restenosis following angioplasty is not considered.
U.S. Pat. Nos. 5,461,039 and 5,593,971 to Tschollar et al. disclose the use of a cholesterol-lowering drug, alone or in combination with an ACE inhibitor, to inhibit hypertension in a normotensive individual who has insulin resistance. No mention is made of combining cholesterol-lowering drugs with inhibitors of the renin-angiotensin system other than ACE inhibitors or with aspirin. In addition, the disclosed methods are limited to normotensive individuals who are insulin resistant, and no mention is made of directly preventing cardiovascular events.
Eisman et al., in U.S. Statutory Invention Registration No. H1286, disclose a method for treating peripheral atherosclerotic disease and/or intermittent claudication by use of one or more cholesterol-lowering drugs by themselves or together with an ACE inhibitor, or by use of an ACE inhibitor alone. No mention is made of combining cholesterol-lowering drugs with inhibitors of the renin-angiotensin system other than ACE inhibitors or with aspirin. The treatment or prevention of cardiovascular disorders other than peripheral atherosclerotic disease and/or intermittent claudication is not considered.
Bergey et al., in European Patent Specification EP 0 457,514 B1, disclose the use of a cholesterol-lowering drug together with an ACE inhibitor to prevent, stabilize, or cause regression of atherosclerosis. No mention is made of combining cholesterol-lowering drugs with inhibitors of the renin-angiotensin system other than ACE inhibitors or with aspirin. The treatment or prevention of cardiovascular disorders other than atherosclerosis is not considered.
U.S. Pat. No. 6,235,311 to Ullah et al. discloses pharmaceutical compositions containing a statin (HMG CoA reductase inhibitor) plus aspirin, optionally containing vitamins B6, B12, or folic acid, and methods of their use for: lowering serum cholesterol; preventing, inhibiting, or treating atherosclerosis; or reducing the risk of or treating a cardiovascular event or disease, coronary artery disease, or cerebrovascular disease. This reference makes no mention of, or considers in any way, inhibitors of the renin-angiotensin system.
Coniglio et al., in U.S. Pat. No. 6,248,729, disclose a method for preventing a cerebral infarction by administering to a patient a combination of an ADP-receptor blocking antiplatelet drug, an antihypertensive agent (such as an angiotensin II antagonist, an ACE inhibitor, or an ACE/NEP inhibitor), and optionally aspirin. Pharmaceutical compositions comprising combinations of these agents are also disclosed. The disclosed methods and compositions, however, require an ADP-receptor blocking antiplatelet drug (which does not include aspirin) and do not mention or consider cardiovascular events other than a cerebral infarction.
Schoelkens et al., in International Patent Publication No. WO 01/15674, disclose the use of an inhibitor of the renin-angiotensin system, optionally together with another antihypertensive drug, a cholesterol-lowering drug, a diuretic, or aspirin, in the prevention of cardiovascular events. Also disclosed is a combination product for this purpose containing an inhibitor of the renin-angiotensin system and a cholesterol-lowering agent. Further disclosed is the use of an inhibitor of the renin-angiotensin system together with another antihypertensive, or a cholesterol-lowering agent, or a diuretic, or aspirin in the manufacture of a medicament for the prevention of cardiovascular events. Never mentioned or considered is the possibility of combining three or more active agents, either in a method for the treatment of a patient or in the manufacture of a pharmaceutical product. Even though certain inhibitors of the renin-angiotensin system, cholesterol-lowering agents, and aspirin are mentioned, and combination therapies involving inhibitors of the renin-angiotensin system together with a cholesterol-lowering agent or aspirin are disclosed, no consideration is made of combining all three.
Accordingly, it is a primary object of the invention to provide a pharmaceutical composition that overcomes the limitations of the above-described formulations and dosage forms.
One object of the invention is to provide a method for treating a patient at elevated cardiovascular risk, such method involving the daily oral administration of a pharmaceutical composition, preferably a single pharmaceutical composition, containing therapeutically effective unit dosages of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, aspirin, and optionally one or more B vitamins.
Another object of the invention is to provide such a method wherein the elevated cardiovascular risk as is an elevated risk of cardiac arrest, myocardial infarction (including acute or chronic myocardial infarction), coronary heart disease, ischemia, stroke, claudication, peripheral vascular disease, restenosis, and/or atherosclerosis.
Still another object of the invention is to provide such a method wherein the patient at elevated cardiovascular risk has systemic lupus erythematosus, is or has been a cigarette smoker, is diabetic, is on hemodialysis, or has received an organ transplant.
Still another object of the invention is to provide such a method wherein the cholesterol-lowering agent is an HMG CoA reductase inhibitor, the inhibitor of the renin-angiotensin system is an ACE inhibitor or an angiotensin II antagonist, and the composition contains vitamin B6, vitamin B12, and folic acid.
Yet another object of the invention is to provide a method for increasing the likelihood that a patient suffering an acute myocardial infarction (MI) will survive, the method comprising administering the pharmaceutical composition to the patient at the time of the MI.
It is another object of the invention is to provide a once-daily orally administrable pharmaceutical composition for treating a patient at elevated cardiovascular risk, the composition comprising a combination of therapeutically effective unit dosages of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, aspirin, and optionally one or more of vitamin B6, vitamin B12, and folic acid, plus a pharmaceutically acceptable carrier, wherein each unit dosage is a daily dose.
Another object of the invention is to provide such compositions wherein the cholesterol-lowering agent is an HMG CoA reductase inhibitor and the inhibitor of the renin-angiotensin system is an ACE inhibitor or an angiotensin II antagonist.
It is still another object of the invention to provide such compositions wherein all three of vitamin B6, vitamin B12, and folic acid are incorporated therein.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
The present invention provides a once-daily oral dosage form containing a combination of a therapeutically effective unit dose of a cholesterol-lowering agent, a therapeutically effective unit dose of an inhibitor of the renin-angiotensin system, and a therapeutically effective unit dose of aspirin, optionally further combined with at least one vitamin B substance, and a method for treating a patient at elevated cardiovascular risk by administering the dosage form on a daily basis. Prior to the present invention, patients at elevated cardiovascular risk lacked adequate treatment to reduce their risk of cardiovascular events due to the unavailability of effective, safe, and convenient drugs for this purpose. The present invention, by contrast, provides a safe and effective method for reducing the risk of cardiovascular events in these patients, by providing a single oral dosage form containing the aforementioned combination of active agents, which is conveniently administered once per day. Such a simple regimen has a high degree of patient compliance, leading to substantially improved efficacy. The combination of three or more active ingredients provides the additional advantage of possibly allowing reduced dosages of the active ingredients, increasing the safety of the therapy.
In a preferred embodiment, the dosage form of the invention comprises:
approximately 10 mg to approximately 80 mg, preferably approximately 25 mg to approximately 60 mg, of an HMG CoA reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin;
approximately 1 mg to approximately 20 mg, preferably approximately 5 mg to approximately 15 mg, of an ACE inhibitor selected from the group consisting of captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and trandolapril;
approximately 20 mg to approximately 600 mg, preferably approximately 20 mg to approximately 150 mg, of aspirin; and, optionally, at least one of
approximately 25 mg to approximately 75 mg, preferably approximately 40 mg to approximately 60 mg, of vitamin B6;
approximately 0.25 mg to approximately 2 mg, preferably approximately 0.5 mg to approximately 1.5 mg, of vitamin B12; and
approximately 0.5 mg to approximately 8 mg, preferably approximately 1.5 mg to approximately 5 mg, of folic acid.